The broad, long-term objective of the research described in this proposal is to develop the means to apply the high linear energy transfer boron-10 neutron capture reaction [10B(n,alpha)7Li] to cancer therapy, using monoclonal antibodies as vehicles for the selective delivery of boron-10 atoms to tumors. It has been calculated that in order for this approach to be successful about 10/3 boron-10 atoms must be attached to each immunoprotein without compromising its ability to localize efficiently in tumor. Although several groups have demonstrated the conjugation of antibodies with the required amount of boron, in every case liver uptake of the immuno-conjugates has been greatly increased at the expense of tumor targeting. The present proposal describes a mature systematic approach to this problem that involves the coordination and integration of research in chemistry and immunology. The boron compounds to be used in this research are homogeneous oligomeric boron-rich phosphate diester derivatives (boron-rich 'trailers'). Compounds of this class are derived from simple precursors and can be simply and efficiently assembled using automated DNA synthesis instruments. Characterization of the effects of various structural alterations (monomer geometry, boron content, and hydrophilicity; macromolecular connectivity; charge and charge distribution) upon the boron-rich trailers will facilitate the selection of only the most promising trailer reagents (very hydrophilic, low non-specific binding to protein, minimal uptake in liver as well as other organs) for conjugation to immunoproteins. Antibody engineering will be used to generate immunoprotein delivery vehicles for the boron-rich trailer reagents. Whole antibodies as well as their immunoreactive fragments (generated via antibody engineering) specific for the tumor-associated carcinoembryonic antigen (CEA) will be studied. Each of these proteins will be endowed with exposed, reactive thiol groups for site-specific conjugation with boron-rich trailer molecules. The reaction of the thiol groups on these immunoproteins with appropriately functionalized boron-rich oligophosphates will afford a wide variety of boron-rich immunoconjugates, and the in vitro properties of these novel compounds will be extensively characterized. The biodistribution and tumor-targeting ability of the best behaved boron-rich immunoconjugates will be thoroughly evaluated, and the most promising immunoconjugates will be ultimately examined in studies designed to demonstrate their efficacy in BNCT. These systematic studies will lead to the optimization of the boron-rich trailer reagents, the conjugation chemistry, and the immunoprotein delivery vehicles, and will ultimately demonstrate the viability of the immunoconjugate approach to the boron neutron capture therapy of cancer.